In this work, high-cycle fatigue behavior of friction-stir welded AA6061-T6 was studied. An emphasis has been made on the inter-relationship between microstructure, residual stress and fatigue resistance. The welds were produced under optimized conditions, including a combination of relatively high welding temperature and rapid cooling rate, and subsequently undergone a standard post-weld aging heat treatment. The optimized welds exhibited excellent fatigue performance that was comparable (or even superior) to that of the base material. This result was attributed to a considerable grain refinement in the stir zone, subtle material softening in the heat-affected zone as well as to significant residual stress generated during the optimized FSW.